KR20170056573A - Injectable microparticles for hyper-localized release of therapeutic agents - Google Patents

Abstract

Injectable drug-loaded microparticles, pharmaceutical compositions thereof, and methods for using the same in body compartments or for systemic administration are described herein.

Description

≪ Desc / Clms Page number 1 > INJECTABLE MICROPARTICLES FOR HYPER-LOCALIZED RELEASE OF THERAPEUTIC AGENTS -

Cross-reference to related application

This application claims the benefit of U.S. Provisional Application No. 62 / 052,959, filed September 19, 2014, 119 (e), which is incorporated herein by reference in its entirety.

The present invention relates to an injectable sustained release composition comprising drug loaded microparticles, and a method of delivering the same.

Drug loading microspheres have been used for sustained release of therapeutic agents. However, truly local release is difficult to achieve and rupture release remains as one of the major factors causing undesirable systemic side effects. Thus, there is a medical need to not only prolong the local action duration of a therapeutic agent, but also effectively reduce systemic side effects associated with its administration.

A pharmaceutical composition, injectable dosage form, and pain in a body compartment, such as joint space, epidural space, vitreous cavity, surgically created space, intracranial space or space adjacent to an implant surgical site or solid tumor, infection, malignant tumor Lt; RTI ID = 0.0 > and / or < / RTI >

The present invention provides a diffusion driven release mechanism based on a membrane that is large enough to allow drug loading, but with drug particle sizing small enough to be injected.

As provided herein, a "drug" or "therapeutic agent" is coated with a semipermeable polymeric shell and injected into a body compartment. Water then diffuses through the polymer and dissolves the drug core (D) to produce a saturated solution inside the membrane (C), causing an intrinsic sink condition outside the particle (c). This concentration gradient induces a constant (zero order) release of the drug from the drug particle as long as some drug core remains to maintain the saturated solution. The release period can be adjusted by changing the permeability of the polymer coating.

The present invention also relates to the use of a diaphragm block (mainly a palliative canine pain); Epidural blockade (palliative treatment); And to the use of local anesthetics for this purpose with a focus on plexus block (i.e. brachial plexus) for analgesia, anesthesia, limb and finger grafting for improved blood flow.

The present invention also relates to the injection of a therapeutic agent (e.g., a CNS modulator focused on GABA receptors) locally in a nerve injury site that includes intracranial injection and possibly also subcutaneous injection.

The present invention also relates to a systemic delivery (subcutaneous) and topical application (combination and / or application) using one or more of the antibiotic's implants (pacemaker, defibrillator, orthopedic implant, artificial heart) Lt; / RTI >

The present invention also relates to the local delivery of powerful chemotherapeutic agents and hormones for the treatment of malignant tumors.

The following drawings illustrate embodiments in which the same reference numerals denote the same parts. Embodiments are illustrated by way of example and are not to be construed as limitations on any attached drawings.
Figure 1 shows diagrammatically the microparticles of core / shell morphology.
Figure 2 shows the in vitro release profile of fluticasone propionate as uncoated powder, uncoated crystals and coated crystals.
Figure 3a shows the emission profile of fluticasone propionate microparticles subjected to heat treatment at various temperatures.
Figure 3b shows the release half-life of microparticles of fluticasone propionate subjected to heat treatment at various temperatures.
Figures 4a and 4b show particle size distributions of fluticasone propionate microparticles compared to the particle size distribution of triamcinolone hexasatonide (TA) (Kenalog (TM)).
Figure 5 is a graph showing the relative amounts of fluticasone propionate and PVA in the microparticles by ¹ H NMR analysis.
Figure 6 is a graph showing the dissolution profile of triamcinolone hexasatonide (TA) compared to the sustained release (SR) formulation of fluticasone propionate (FP) according to an embodiment of the present invention.
Figure 7 is a graph showing plasma platigasin (FP) level, lubricant FP level after injection of a 20 mg formulation into a knee joint in a positive amount compared to intra-articular pharmacokinetics of triamcinolone hexasatonide (40 mg) from a human subject.
Figures 8a, 8b and 8c show the results of a histological examination of injected joints in an amount that does not show any abnormality.
Figure 9 shows local concentrations in tissues and lubricants of the knee joints for a period of 60 days after a single infusion of low dose fluticasone propionate. Plasma concentrations were too low to be detected.
Figure 10 shows the local and regional concentrations in the tissues and lubricants of the knee joints and plasma concentrations for a period of 60 days after a single infusion of high dose fluticasone propionate.
Figure 11 shows the plasma concentrations of fluticasone propionate after a positive knee < RTI ID = 0.0 > joint < / RTI > The microparticles for each injection were subjected to different heat treatments before being formulated with the injectable composition.
Figure 12 shows plasma concentrations of fluticasone propionate in the knee joints over a period of 45 hours after a single infusion. The pharmacokinetic (PK) curve represents the absence of an initial burst.

The pharmaceutical compositions, injectable dosage forms, and topical inflammation, pain (including post-surgical pain) in the body compartments such as joint space, epidural space, vitreous body of the eye, surgical space, intracranial space or space adjacent to the implant, ), Infection, methods of using it for the treatment or management of malignant tumors are described herein.

The pharmaceutical composition comprises a plurality of microparticles with core / shell morphology. In particular, the particulate comprises a crystalline drug core of the therapeutic agent and a polymer shell encapsulating the crystalline drug core. As discussed in more detail herein, injectable microparticles have a high drug-loading, a narrow size distribution, and a sustained release of the order-of-release, as defined herein, within the body compartment, Emission profile. The release profile depends on the pain or the corresponding therapeutic agent. Therapeutic agents for pain management may be released for a period of 2 to 12 months, while antibiotics may be released for a period of 3 to 7 days.

Sustained release mechanisms are based on dissolution. It has been found that water from a body compartment diffuses through the polymer shell and partially dissolves the crystalline drug core when drug particles coated with a semipermeable polymer shell are injected into the body compartment without attempting to associate it with any particular mechanism of action lost. As a result, a saturated solution of the drug is formed inside the polymer shell. Because there is essentially a syngeneic state in the body fluids into which the microparticles are injected and stay (e.g., lubrication fluids when the body compartment is a joint), a concentration gradient is created that continuously leads the drug out of the microparticles and into the body fluids. As long as some drug core remains to maintain a saturated solution in the polymer shell, a constant (i.e., zero order or pseudo-zeroth order) release of the drug from the coated microparticles is obtained.

Also disclosed herein are methods of reducing or managing pain resulting from, for example, surgical pain, chronic pain, or pain of neuropathy by administering a dosage form injectable into the body compartment. Advantageously, the release maintains a low or undetectable systemic level of therapeutic agent while ensuring a localized level of treatment, which is highly localized in the local tissue or fluid medium of the body compartment to provide long-term action.

Justice

The singular "a, an" is used herein to refer to one or more than one (i.e., at least one) of the singular grammatical objects. By way of example, "an element" means one element or more than one element.

The term " plurality "means" two or more "unless explicitly stated otherwise. For example, "plurality" may simply refer to a plurality of fine particles (two or more) or a whole group of fine particles in a given composition or dosage form, for example, for purposes of calculating the size distribution of the fine particles .

As used herein, unless otherwise specifically indicated, the word " or "means " either / or ", but is limited to" It is not. Instead, "or" may also mean "and / or ".

As used herein, the terms "therapeutic agent" and "drug" are used interchangeably and refer to any agent capable of producing a therapeutic effect or advantage. The term "slow release" or "extended release" when used in connection with a therapeutic agent or drug (e.g., a chemotherapeutic agent) is used interchangeably. Sustained release means that the therapeutic agent is continuously released over an extended period of time after administration of a single dose to provide a long term therapeutic effect throughout the release period.

"Sustained release" is in contrast to bolus-type administration in which the total amount of active agent / material becomes biologically available at one time. Nonetheless, "sustained release" may include earlier, faster release and later, longer, extended release, slower release. As will be discussed in more detail below, the construction of the microparticles may result in an earlier, faster release (e.g., rupture release) to achieve a substantially constant release profile (i.e., a zero-order or similar zero- ≪ / RTI > and to extend the extended release period.

All non-zero emissions are not within the meaning of "sustained release". Rather, "slow release" should provide at least a therapeutically effective amount of a therapeutic agent (as defined herein) during the release period. It is to be understood that the minimum therapeutically effective amount of the therapeutic agent will depend on the severity of the pain to be resolved.

"Sustained release period" means the total release period during which the local concentration of the therapeutic agent is maintained at or above a therapeutically effective amount. Of course, the desired sustained release-release period may vary depending upon the disease or condition being treated, the nature of the therapeutic agent, and the condition of the particular patient being treated. Thus, the desired sustained release-release period can be determined by the primary care physician.

By "topical concentration" is meant the concentration of the drug in the body compartment (as defined herein), including the tissue or body fluids concentration of the body compartment.

"Plasma concentration" means the concentration of drug in plasma or serum. The injectable microparticles are capable of highly localized release over a long period of time while maintaining a low plasma concentration, e. G., A concentration sufficiently low to minimize undesirable systemic side effects during the sustained release period.

Within the scope of the present invention, the sustained release of the therapeutic agent is achieved due to the unique structure of the particulate, which is core / shell morphology. In particular, the crystalline drug core of the therapeutic agent is encapsulated in a polymeric shell comprised of one or more polymer coatings, each permeable to the therapeutic agent. In a preferred embodiment, all layers comprise the same polymer. In another embodiment, two to four layers of the polymer are coated on the therapeutic agent, while each layer is augmented to slow the release of the active ingredient and collectively provide the desired sustained release. In addition, sustained release of the therapeutic agent is achieved by aligning this delivery platform with the aqueous or sink environment of the body compartment.

As used herein, "patient" or "subject" to be treated by a method according to various embodiments may refer to any human or non-human animal, for example, a primate, a mammal, and a vertebrate.

The phrase "therapeutically effective amount" when applied to a body compartment in the form of coated microparticles as defined herein refers to the degree of symptom reduction in the body compartment of the patient, which may be applicable for any medical treatment (At a reasonable benefit / risk ratio). The effective amount of the therapeutic agent may vary depending on factors such as the type and severity of the arthritis to be treated, its progress, the degree of pain exerted on the patient, the particular particulate administered, the active agent and / or the size / age / sex of the subject. One skilled in the art can determine the effective amount of a particular therapeutic agent empirically according to methods known in the art. &Quot; Therapeutically effective amount "means the amount of therapeutic agent localized in the body compartment, unless otherwise specified.

A "minimal therapeutically effective amount" is the minimum amount of a therapeutic agent capable of providing a therapeutic effect (e.g., pain relief or anti-inflammation).

"EC50" is, for example, the concentration of a therapeutic agent that produces 50% of the maximal effect in pain relief.

A "unit dosage form" refers to a physically distinct unit (e.g., loaded in a syringe cylinder) suitable as a unit dose for a human subject, wherein each unit is combined with a pharmaceutically acceptable vehicle ≪ / RTI > The amount of therapeutic agent is calculated to produce the desired therapeutic effect over the desired period of time.

The term "treating" is art-recognized and includes treating a disease or condition by alleviating at least one symptom of the particular disease or condition, even if it does not affect the underlying pathology.

"Body compartment" means a space or cavity within the body of a vertebrate (including a human being) accessible by injection. Typically, the body compartment is at least half-enclosed or entirely surrounded by hard or soft tissue (e.g., bones, membranes, ligamentous structures) defining the space. Soft tissue is typically presented and can have varying degrees of vascularization. Body compartments typically contain body fluids, such as intra-articular lubricants, epidural spinal fluid, and ocular vitreous body fluids. Body fluids can not communicate with or communicate outside the body compartment. More specifically, the body compartment may be a naturally occurring anatomical space such as a lubricant joint, an epidural space, and an ocular vitreous. In addition, the body compartment may be any space near the implant that can be accessed through surgery (e.g., a pocket for inserting an implantable device, soft tissue implant such as a breast implant, etc.) or implantation. The body compartment may also be a space near the tumor, particularly a solid tumor. The body compartment can also be intracranial. The body compartment may also be a site near the surgical site or a surgical site.

The term "synovial joint" means an articulation of two or more bones. The segment is defined by a lubricant cavity containing a large amount of lubricant, is lined with synovial membrane, and is surrounded by fibrous capsules. Opposite bone surfaces are covered with a cartilage layer, respectively. Cartilage and lubricants reduce friction between the articular bone surfaces and enable smooth movement. Lubricating fluid joints can be further divided into these forms, which control the motion they allow. For example, the hinge joint acts like a door hinge, allowing bending and stretching only on a single plane. For example, there is an elbow between the humerus and the ulna. Like the buttocks, the mortise joint allows movement in multiple planes at the same time. Upper (or elliptical) joints, such as knees, allow movement from one location to another in some locations, but not in other locations. For example, it is impossible to rotate in a straight knee, but it can be rotated when the knee is bent. The interphalangeal joints, such as the elbows (between the radial and ulnar), allow one bone to rotate around the other. The saddle joints, such as the thumb (between the metacarpals and the sagittal), are so named because of their saddle shape and allow movement in various directions. Finally, the sliding joints, such as the wrist of the wrist, allow a variety of movements but do not allow large distances.

The lubrication fluid joint is composed of the shoulder (arm and acromioclavicular), elbow (chuck - upper arm, ureter and proximal yaw ulna), forearm (yaw ulna, (Lateral), medial (lateral), medial (lateral), medial (lateral), medial (lateral), medial Metatarsophalangeal joints, metatarsal joints, and valgus joints).

"Intra-ocular" and "intravitreous" are used interchangeably herein to refer to the vitreous of the eye.

As used herein, the term "microparticle" means a particle having an average dimension of less than 1 mm. Although the particulate is substantially spherical in some embodiments, the particulate can be any solid geometric shape, including, without limitation, needle, elliptical, cylindrical, polyhedral and irregular forms, which does not contradict the principles of the present invention.

The microparticles are coated drug particles that are crystalline, polycrystalline or amorphous. As used herein, the microparticles have a "core / shell" morphology as shown diagrammatically in FIG. 1 wherein the drug core 10 is encapsulated in a polymer shell 20, and the polymer shells are made of the same or different polymers One or more thin coatings (two coatings 25 and 30 are shown). Importantly, the polymer shell 20 is formed of a polymer coating that is not miscible with the drug core, so that the interface 40 between the drug core and the polymer shell is sharp with the least amount of drug or polymer (e.g., drug Or less than 5%, or less than 1%, or less than 0.5% of the total weight of either polymer. When the drug core contains a highly hydrophobic drug, the polymer shell preferably contains at least one hydrophilic polymer. Conversely, when the drug core contains a highly hydrophilic drug, the polymer shell preferably contains at least one hydrophobic polymer. Although the polymer shell may eventually be degraded, it must maintain its structural integrity throughout the sustained release period to maintain the environment for dissolving the drug core to form a saturated solution.

The term " core particle "and" drug core "as used herein means interchangeably of a single crystal or multiple crystals of a drug, or preformed particles which may be amorphous particles. The drug core is encapsulated into a polymer shell. The core particles may additionally include, without limitation, binders, buffers, antioxidants, excipients and other compounds including additional active pharmaceutical ingredients. The core particles may be a single large crystal, a plurality of crystals, or a mixture thereof. In a preferred embodiment, the drug core is a substantially pure drug (i.e., at least 90%, or at least 95%, or at least 98% of the total weight of the drug core is a drug). In a preferred embodiment, the drug core is a 100% crystalline drug.

"Polymer shell" as used herein includes one or more polymer coatings. "Polymer coating" means a thin layer of linear, branched, or crosslinked macromolecules having a continuous surface surrounding the crystalline drug core. Referring to FIG. 1, polymer coatings 25 and 30 are coated sequentially and concentrically on drug core 20. Although the drug core 20 and the immediately adjacent polymer coating 25 should be incompatible, the polymer coatings 25 and 30 themselves can intimately contact each other, providing structural integrity during the sustained release period Allowing a certain degree of miscibility at the interface 50 between adjacent coatings to form a polymeric shell 20 of coherent structure. The polymer shell should substantially surround or seal the core particles.

"Coating solution" means a solution of a previously formed polymer (e.g., a commercially available polymer) and is suitable for coating the drug core according to methods known in the art, such as, for example, fluid bed coating.

The term "permeable" as used herein means to allow the passage of molecules of the therapeutic agent into the diffusion but not the body fluid flow.

As used herein, the term "semi-permeable" means permeable to some molecules other than to other molecules. The semipermeable polymer shell as used herein is at least permeable to water and to the therapeutic agent in the coated microparticles of the present invention.

"Dissolution half-life" is an in vitro measurement of the dissolution characteristics of the fine particles. Specifically, the dissolution half-life is the amount of time taken for half of the initial loading of the drug in the particulate to dissolve and dissolve into the dissolution medium under a particular set of dissolution conditions. Although performed in vitro, the dissolution half-life is nonetheless a recognized industry-recognized factor that is nonetheless considered in predicting in vivo release characteristics and may represent an accelerated model of sustained release behavior in vivo. In particular, the dissolution half-life provides a qualitative tool for predicting in vivo behavior by comparing the dissolution half-life of various formulations. For example, a formulation that exhibits a longer dissolution half-life in vitro is expected to exhibit a longer sustained release period in vivo. Unless otherwise specified, the dissolution system used to measure the dissolution half-life of the microparticles is the USP Type II (paddle).

"Dissolution profile" is a graphical representation of the percent solubility measured in hours. Besides providing quantitatively the amount of dissolution as a function of time, the curvature of the profile shows qualitatively the extent of the initial burst. For example, a sharp increase in flexion represents a faster initial release (burst) as compared to a softer lift.

"Vehicle" means a non-toxic carrier, adjuvant or solvent in which the particulate is suspended. The vehicle does not alter or impair the pharmacological activity of the therapeutic agent in which it is formulated. Pharmaceutically acceptable carriers or vehicles that may be used in the composition include, but are not limited to, water, physiological saline, hyaluronic acid, and the like. The term "biocompatible " as used herein means to be characterized as not causing toxic, deleterious or immunological reactions when contacted with living tissue, particularly human or other mammalian tissues.

The term "biodegradable " as used herein means that it is capable of partially or completely dissolving or decomposing in living tissue, particularly in a human or other mammalian tissue. The biodegradable compound can be decomposed by any mechanism including, without limitation, hydrolysis, catalysis and enzymatic action.

The term "substantially degraded " as used herein in connection with a polymer coating means that about 50% of the chemical bonds resulting from the polymerization of the polymer forming solution forming the polymer coating have been broken down to such an extent that it has disintegrated.

The term "structural integrity " as used herein in connection with the polymeric shell of the present invention means that there remains a continuous surface that is semiperiphilic and allows diffusion but does not include any discontinuity that allows bodily fluid flow it means.

The term "external environment " as used herein means a localized area or region of tissue surrounding the coated microparticles of the present invention after direct injection into the body compartment.

The term "saturated" as used herein means containing the maximum concentration of a solute (e.g., active pharmaceutical ingredient) that can be dissolved at a given temperature.

The term "substantially insoluble" as used herein means having a solubility of less than 1 part solute per 1000 parts solvent.

The term "hydrophobic " as used herein means having a lower affinity for an aqueous solvent than an organic solvent.

The term "hydrophilic " as used herein means having a lower affinity for an organic solvent than an aqueous solvent.

The term "pseudo-zero order kinetics ", as used herein, is intended to encompass the term " pseudo-zero order kinetics " between zeroth order (i.e. concentration independent) or zero- order to 1- Release of a therapeutic agent which indicates the kinetics of the active agent, wherein the concentration is based on the total amount of active pharmaceutical ingredient contained within the coated microparticles. In some embodiments, the release of active pharmaceutical ingredients exhibits kinetics closer to zero-order than 1-order kinetics.

As used herein, citation of the numerical range of a variable is intended to indicate that the invention can be practiced with a variable equivalent to any value within this range. Thus, for essentially discrete variables, the variable may be equal to any integer in the numerical range including the end point of the range. Similarly, for essentially continuous variables, the variable may be equal to any real number in the numerical range including the end point of the range. By way of example, and without limitation, a variable described as having a value of 0 to 2 may take a value of 0, 1 or 2 if the variable is essentially a separate variable and 0.0 , 0.1, 0.01, 0.001, or? 0 and? 2.

Particulate

The particulates of the core / shell morphology described herein are configured to exhibit a sustained release profile uniquely suited to highly localized extended delivery of the therapeutic agent within the body compartment. In particular, the particulate comprises: (1) at least 70% by weight of the drug core, wherein the drug core comprises at least one therapeutic agent; And (2) a polymer shell that encapsulates the drug core, whereby the polymer shell is contacted with the crystalline drug core but is incompatible.

The sustained release profile in vivo correlates with the in vitro dissolution characteristics of the microparticles, which is determined by the solubility of the drug core, the permeability, the degree of crosslinking of the polymer shell, and the rate of degradation, in particular.

Drug core

May include one or more therapeutic agents in any one of the following classes. In a preferred embodiment, the drug core is a pure drug as defined herein.

i. Local anesthetic

In some embodiments, the therapeutic agent is selected from the group consisting of a scaffold block (mainly a palliative cancer pain); Epidural blockade (palliative treatment); And at least one topical anesthetic (amide) for plexus block (i.e., brachial plexus) and vascular procedures for analgesia, anesthesia, limb and finger grafting to improve blood flow.

Specifically, the therapeutic agent may be lidocaine, bupivicaine, and lidofibicaine. Other amine-containing "cytokine" type drugs, for example, cents unit acridine, tetracaine, Novo Cain ^R (Novocaine ^R) (procaine), the arm Cain, amorphous ranon, amyl Cain, benok when carbonate, chopping ethoxy But are not limited to, carrageenan, catechol, catechol, catechol, carbinol, catechol, carbinol, catechol, But are not limited to, glutamate, glutamate, glutamate, glutamate, glutamate, glutamate, glutamine, glutamate, glutamine, glutamate, - an adrenergic receptor antagonist, an opioid analgesic, butanylicaine, ethyl aminobenzoate, tosin, hydroxyprocaine, isobutyl p-aminobenzoate, nepaline, octacaine, orthocaine, oxetazine, parenthoxycaine, Phenacine, piperocaine, polydocanol, But are not limited to, pramoxine, prilocaine, prilocaine, propanocaine, proparacaine, propipocaine, pseudococaine, pyrocaine, salicyl alcohol, parethoxycine, pyridocaine, lithocaine, tolcaine, , Anticonvulsants, antihistamines, atticins, cocaine, procaine, amethocaine, chloroprocaine, macauin, chloroprocaine, etidocaine, prilocaine, lignocaine, benzocaine, zolamine, , A dibucain, a pharmaceutically acceptable salt thereof, or a mixture thereof.

ii. Central Nervous System (CNA) formulation

The CNS drug may be administered topically, possibly also subcutaneously, to the area of nerve injury. Suitable CNS preparations are CNS modulators that are focused on GABA receptors. In certain embodiments, the CNS formulation can be gabapentin, pregabalin (lilica), topiramate (topazam), valproic acid (valproate) or oxcarbazepine. The CNS drug may also be a neurotransmitter, for example, dopamine, a dopamine agonist or a dopamine precursor such as L-3,4-dihydroxyphenylalanine.

iii. Antibiotic

Antibiotics can be administered systemically (subcutaneously) or topically and are combined and / or combined with implants such as, for example, pacemakers, defibrillators, orthopedic implants, artificial hearts, and the like.

Certain antibiotics include first-generation cephalosporins such as kappazoline, cephalexin; Second-generation Sepharose rhinitis, such as Sephroxime, Sipoxitin, and Cefprozil; And beta-lactam antibiotics such as cephalosporin, including the third generation sepharose prism, such as cechimic, ceftazidime, ceftriaxone, and cytotoxin.

Additional examples of antibiotics include the penicillin family and combinations comprising it, for example, piperacillin and tezacobamine.

iv. Chemotherapeutic agent or antineoplastic agent

In some embodiments, the invention provides for local delivery of a potent chemotherapeutic agent and a hormone provided for the treatment of malignant tumors. Highly localized delivery of the drug to the capsule maximizes the effect and minimizes any side effects.

Any conventional therapy for malignant tumors can be formulated with a drug / shell construct for localized release. Types and locations of malignant tumors include, for example, prostate cancer drugs (e.g., antiandrogens and chemotherapeutics); Brain tumor drugs (eg, steroids and chemotherapeutic agents for discrete tumors in the brain, regardless of whether they are benign or malignant); Ovarian cancer drugs; Spinal tumor drugs; And osteosarcoma drugs.

The crystalline drug core may also be a corticosteroid drug, for example, which appears to exhibit pseudo-zero order localized release at minimal systemic concentrations. The method of manufacture, release behavior and properties are described in PCT / US2014 / 031502, the entirety of which is incorporated herein by reference.

A preferred system is for formulating therapeutic agents, and since this is a "dissolution-based delivery system ", relatively low solubility therapeutic agents are preferred.

In general, the crystalline form of a given therapeutic agent has a much lower solubility than the amorphous form of the same drug, resulting in a longer dissolution half-life and fewer initial bursts. Thus, the drug core may be a single large crystal or an aggregate of a plurality of small crystals. The crystalline drug core coated with the polymer shell further elongates the dissolution time and further minimizes any initial burst.

Therapeutic agents are used in therapeutically effective amounts, which vary widely depending on the particular agent used. The amount of the agent to be incorporated into the composition also depends on the desired release profile, the concentration of the agent required for the biological effect, and the length of time that the biologically active agent is to be released for treatment.

There is no critical upper limit on the amount of therapeutic agent introduced, except for the acceptable viscosity of the solution or dispersion to maintain the desired physical properties for the composition. The lower limit of the formulation introduced into the polymer system depends on the activity of the therapeutic agent and the length of time required for treatment. Thus, the amount of therapeutic agent should not be so large as to fail to produce the desired physiological effect or to release in such a way that it can not be controlled.

An important advantage of injectable microparticles is a much higher drug loading than previously known drug-loaded microparticles. In other words, each particulate has a relatively lesser fraction as a polymer shell and has a relatively larger fraction as a drug core.

Moreover, the drug core is a substantially pure drug because the drug core is made from a recrystallized drug in the form of either a single large crystal or an aggregate of smaller crystals. Thus, "substantially pure" means that at least 90%, or at least 95%, or at least 98%, or 100% of the total weight of the drug core is a crystalline form of the drug.

Thus, in various embodiments, within each microparticle, 70-97% of the total weight of the microparticles is the therapeutic, and 3-30% is the polymer. In one embodiment, the drug core is at least 70% of the total weight of the microparticles, and less than 30% of the total weight of the microparticles is a polymer shell. In another embodiment, the drug core is at least 75%, at least 80%, at least 85%, at least 90% or at least 95% of the total weight of the microparticles and the remainder of the microparticles are polymer shells.

Polymer shell

The polymer shell comprises a polymer coating coated with one or more concentric circles or continuously of the same or different polymers. The standard biocompatible and biodegradable polymer coatings known in the art can be used to the extent that they meet the requirements described above for maintaining permeability and / or structural integrity during the desired sustained release period. While the sustained release period is enhanced within the scope of the present invention through the advantageous and unexpected interaction of the drug loading and body compartment described herein with the dissolution-based delivery system described herein, Additional factors play a role in supporting the excellent effect of the process of the present invention:

· Solubility of therapeutic agent

The size of the core particles and / or the amount of the therapeutic agent initially present in the core particles

The presence of other compounds in the core particle affecting the release rate of the therapeutic agent

The permeability of the polymer coating (s) to the therapeutic agent

Rate of decomposition of polymer coating (s) and other factors.

As is known in the art, both the permeability and biodegradability of the polymer coating are influenced by the choice of polymeric material (e.g., hydrophobicity or hydrophilicity for the therapeutic agent, degree of instability of the binding under physiological conditions), degree of crosslinking and thickness . In the case of copolymers, the ratio of the different monomers may also be varied to affect permeability and biodegradability.

In a preferred embodiment, suitable biocompatible and biodegradable polymers include polyvinyl alcohol (PVA), poly (p-xylylene) polymers (trademarks registered as Parylene?), Poly (lactic acid) (PLGA), poly (? -Caprolactone) (PCL), poly (valerolactone) (PVL), poly (? - decarboxylic acid) (PDL), poly (1,4-dioxane-2,3-dione), poly (1,3-dioxan- (PHB), poly (hydroxy valeric acid) (PHV), ethylene vinyl acetate (EVA) and poly (beta-malic acid) (PMLA).

In order to influence the permeability and release rate, the polymer coating may optionally be covalently or ionically crosslinked. For example, a monomer comprising a chemical group capable of forming an additional monomer-to-monomer bond may be selected, or a separate crosslinking agent may be included in the polymer forming solution in addition to the monomer. In some embodiments, the crosslinking groups are thermally activated, while in other embodiments they are photoactivated, including light activation by visible or ultraviolet light. Crosslinking groups include, but are not limited to, unsaturated groups such as vinyl, allyl, cinnamate, acrylate, diacrylate, oligoacrylate, methacrylate, dimethacrylate, and oligomethoacrylate groups. Because it is desirable for many therapeutic agents to be hydrophobic and to reduce or avoid dissolution of the drug core into the polymer shell in order to maintain a sharp interface between the core and the shell, the polymer shell may be coated with a hydrophilic polymer . Examples of hydrophilic polymer coatings include, without limitation, polyvinyl alcohol (PVA), poly (ethylene glycol) (PEG), poly (ethylene oxide), poly (vinyl pyrrolidone), poly (ethyl oxazoline) A carbohydrate such as an alkyl cellulose, a hydroxyalkyl cellulose, hyaluronic acid, dextran, heparan sulfate, chondroitin sulfate, heparin or an alginate or a protein such as gelatin, collagen, albumin, Polyamino acids.

Additional examples of suitable polymers may be prepared from monomers selected from the following group: di-phosphate, alkylcellulose, hydroxyalkylcellulose, lactic acid, glycolic acid,? -Propiolactone,? -Butyrolactone, But are not limited to, lactone, pivalolactone, alpha -hydroxybutyric acid, alpha -hydroxyethylbutyric acid, alpha -hydroxyisovaleric acid, alpha -hydroxy- beta -methylvaleric acid, alpha -hydroxycaproic acid, Hydroxyoctanoic acid,? -Hydroxystearic acid,? -Hydroxystearic acid,? -Hydroxy lignoceric acid and? -Hydroxystearic acid,? -Hydroxyheptanoic acid,? -Hydroxyheptanoic acid, - phenol lactic acid.

Because the crystalline drug core constitutes at least 70% by weight of the microparticles, the overall size of the microparticles is mainly determined by the size of the crystalline drug core. Typically, the polymer shell has a thickness of less than about 25%, less than 20%, less than 12%, or less than 5% or less than 3% of the total diameter of the microparticles. Similarly, the weight of the particulate is also predominantly the weight of the crystalline core, leading to a high drug load. In a preferred embodiment, the microparticles comprise 90 to 98% w / w of crystalline drug core and 2 to 10% w / w of polymer shell.

In various embodiments, the microparticles have an average diameter between 50 and 800 mu m, or an average diameter between 60 and 250 mu m, or an average diameter between 80 and 150 mu m.

In a preferred embodiment, the average diameter is 150 占 퐉 with a standard deviation of less than 50% of the average diameter. In another preferred embodiment, the average diameter is 75 m with a standard deviation of less than 50% of the average diameter.

Method of forming fine particles

Methods for forming polymer coatings on particles are well known in the art. For example, standard techniques include solvent evaporation / extraction techniques, underwater drying techniques (see, for example, U.S. Patent 4,994,281), organic phase separation techniques (see, for example, U.S. Patent No. 5,639,480) See, for example, U.S. Patent No. 5,651,990), air suspension techniques, and dip coating techniques.

In the most preferred form, the method of forming particulates is as described in U.S. Patent Publication 2007/003619, which is incorporated herein by reference in its entirety. The crystalline drug core is coated with one or more layers of a polymeric coating that together form a polymeric shell. For example, in one aspect, the PVA polymer coating may be applied using a dip coating technique. Briefly, a 1% coating solution of PVA in water can be formed by dissolving excess PVA in water at 60 ° C for 2 hours (see, for example, Byron and Dalby (1987), J. Pharm. Sci 76 (1): 65-67). Alternatively, a high concentration of PVA solution (e.g., 3 to 4%) can be prepared under reflux while heating to approximately 90 to 100 < 0 > C. After cooling, the microparticles can be added to the PVA solution and shaken, for example, by vortexing or stirring. The microparticles are then removed from the solution, for example, by filtration over a filter paper having a mesh size suitable for the microparticles. Optionally, vacuum-filtration can be used to aid drying. Untreated PVA polymer coatings or films are readily permeable to water and hydrophilic drugs. However, the heating of the PVA causes an increase in crystallinity and a decrease in permeability up to 500 times when the temperature is increased in the range of 100 to 250 DEG C for a period of 0 to 160 hours (see Byron and Dalby (1987), supra) . Thus, in some embodiments, the PVA polymer coating is applied at a temperature of from 100 캜 to 250 캜, from 125 캜 to 175 캜, or from 155 캜 to 170 캜 for a period of from 1 second to 160 hours, 1 to 10 hours, or 5 minutes to 2 hours ≪ / RTI > Most preferably, the heating is 220 [deg.] C or 90% or more for 1 hour depending on the required degree of permeation. Optionally, the coating process can be repeated several times to build a thicker polymer coating. Most preferably, two to five coats are applied to achieve a coating of 5% thickness.

In one embodiment, the microparticles undergo a precise heat treatment step at a temperature in the range of 210 to 230 占 폚 for at least one hour. It has been unexpectedly found that the crosslinking level, and thus the permeability, can be precisely controlled by heating the particulate within this temperature range. More preferably, the heat treatment step is carried out at 220 DEG C for one hour. As discussed below in more detail with respect to dissolution characteristics and Example 6, it is surprisingly found that the heat treated particulates in a certain temperature range (210 to 230 ° C) surprisingly have a degree of crosslinking and permeability which can significantly enhance the dissolution half- Level.

In vitro dissolution characteristics

The structure of the microparticles makes possible a highly localized delivery system based on dissolution. Thus, the in vitro dissolution characteristics, for example, the dissolution half-life, correlate with the sustained release period in vivo.

It is important to understand that the dissolution model is designed to provide accelerated dissolution compared to in vivo release. IVIVC reflecting actual in vivo dissolution could take several months to complete. Nonetheless, accelerated USP type II standard dissolution is useful for providing qualitative comparisons among various formulations and providing a predicator of in vivo release behavior.

PCT / US2014 / 031502 demonstrates how to quantitate the in vitro dissolution characteristics in the context of a corticosteroid drug, and this method can also be extended to quantify the dissolution characteristics of the microparticles described herein.

Figure 2 shows the effect of the particulate structure on the dissolution rate. More specifically, Figure 2 shows the in vitro release profile of uncoated fluticasone propionate powder (amorphous or very small crystals), uncoated fluticasone propionate crystals and coated fluticasone propionate crystals Lt; / RTI > The dissolution profiles clearly demonstrate the tendency of longer dissolution half-lives and smaller initial bursts in amorphous drug versus crystalline drug. This tendency is more pronounced for coated crystalline drug compared to uncoated crystalline drug. Additional details of the dissolution conditions are described in the Example section.

The microparticle formation process also has a significant effect on the dissolution characteristics. In particular, precise heat treatment within a narrow temperature range (e.g., 210 to 230 ° C) provides an unexpectedly significantly enhanced solubility half-life compared to the microparticles that have undergone a heat treatment at temperatures outside of this range. Heat treatment at 160 캜, 190 캜, 220 캜 and 250 캜 in a dissolution test using the US Pharmacopoeia type II apparatus in which the dissolution conditions were 3 mg of fine particles in 200 ml of a dissolution medium of 70% methanol and 30% water at 25 캜 The dissolution profile of the fine particles is shown in FIG. 3A. The heat treated fine particles at 220 DEG C have the slowest and the slowest initial release as compared with the fine particles treated at a temperature of 220 DEG C or lower. Figure 3b shows the dissolution half-life of the microparticles of Figure 3a. As shown, the fine particles heat treated at 220 占 폚 have a significantly longer dissolution half-life (12 to 20 hours) than other fine particles (all less than 8 hours).

These results indicate that the precise heat treatment (i.e., heating within a narrow range of temperatures for a certain period of time) is dependent on the particular structural characteristics that are most effective in enhancing the dissolution half-life, and thus the slow release period, , Including porous and / or permeable).

In vivo  Emission characteristic

PCT / US2014 / 031502 discloses that corticosteroid microparticles can be administered in the body compartment (e.g., intraarticular space) for 2 to 12 months after single injection, more typically for 2 to 9 months after single injection, or for 3 to 6 months Proving that highly localized sustained release of the drug is possible. The results are discussed in more detail in Examples 10-13.

The plasma concentration of the corticosteroid drug may remain unexpectedly far below the local concentration at any given time during the sustained release period and may be below the quantifiable limit after 7 days, although the local concentration may exceed the EC50 of the corticosteroid. Low plasma concentrations minimize any clinically significant HPA axis inhibition.

In addition, corticosteroid microparticles do not exhibit any significant initial burst (locally or systemically), unlike known drug-loaded microparticles.

The method described in PCT / US2014 / 031502 for styling in vivo release properties in the context of corticosteroid drugs can also be extended to quantify the dissolution characteristics of the microparticles described herein.

The in vivo release characteristics may be adjusted so long as the therapeutic agent is capable of retaining the saturated solution in the polymer shell (for example, for 60 days or more, for 90 days or more, or for 180 days or more Zero-order release mechanism of the drug-loaded microparticles described herein, which is released at a substantially constant rate. See also Examples 10 to 13.

In vivo release behavior also correlates with dissolution behavior in vitro. Particularly, microparticles subjected to heat treatment at different temperatures (220 ° C. to 130 ° C.) exhibited in vivo release behavior consistent with their in vitro dissolution. See also Examples 8 and 11.

Pharmaceutical composition

One embodiment is a pharmaceutical composition comprising a plurality of microparticles, wherein the microparticles comprise (1) at least 70% by weight of the crystalline drug core of the microparticles, wherein the crystalline drug core comprises one or more crystals of the therapeutic agent Sex drug core; And (2) a polymeric shell encapsulating the crystalline drug core, wherein the polymeric shell is contacted with or immiscible with the crystalline drug core, wherein the composition is dissolved using the US Pharmacopoeia type II device Wherein the solution exhibits a dissolution half-life of 12 to 20 hours and the dissolution conditions are 3 mg of microparticles in 200 ml of 70% methanol and 30% water dissolution medium at 25 占 폚.

In a preferred embodiment, the crystalline drug core comprises a therapeutic agent, for example, an anesthetic, a central nervous system agent, an antibiotic or a chemotherapeutic agent.

In certain embodiments, the particulates perform a thermal treatment step within a temperature range of 210-230 [deg.] C.

In various embodiments, the average diameter of the microparticles is in the range of 50 占 퐉 to 800 占 퐉, or in the range of 60 占 퐉 to 250 占 퐉, or in the range of 80 占 퐉 to 150 占 퐉.

In a further embodiment, the crystalline drug core is at least 75%, at least 80%, at least 85%, at least 90% or at least 95% of the total weight of the microparticles, the remainder of the microparticles being polymer shells.

In various embodiments, at least 90%, at least 95%, at least 98%, or 100% of the total weight of the drug core is a crystalline form of the drug.

In a preferred embodiment, the diameter of the microparticles in a given pharmaceutical composition may be adjusted or selected to suit a particular route of administration. Thus, in one embodiment, at least 90% of the microparticles have a diameter in the range of 100-300 mu m, providing an injectable composition particularly suitable for epidural injection. Yet another embodiment provides an injectable composition comprising particulates having a diameter in the range of 50 to 100 占 퐉, wherein 90% or more of the particulates are particulary suitable for intraarticular or intraocular injection.

Since the dissolution rate of the crystalline drug is related to the size of the crystals, i.e., the smaller the crystal is, the higher the initial burst rate (see FIG. 2), the population of microparticles in the pharmaceutical composition has a narrow size distribution desirable. Thus, in one embodiment, the plurality of microparticles in the pharmaceutical composition have an average diameter in the range of 50 mu m to 300 mu m and a standard deviation of less than 50% of the average diameter.

In a preferred embodiment, the mean diameter is 150 [mu] m with a standard deviation of less than 50% of the mean diameter (e.g., in the case of epidural injection). In another preferred embodiment, the mean diameter is 75 microns with a standard deviation of less than 50% of the mean diameter (e.g., for intraarticular or intraocular injection).

In a further embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable vehicle in which a plurality of microparticles are suspended. It is preferred that the particulate of the therapeutic agent is mixed with the vehicle just prior to injection so that the therapeutic agent does not have time to dissolve into the vehicle and that there is essentially no or substantially no initial rupture of the drug prior to injection.

Unit dosage form

A unit dosage formulation is a pharmaceutical composition (including all the embodiments described above) having a predetermined amount of drug-loaded microparticles that provides sustained release of the therapeutic agent for a specified period of time after a single injection. The amount of particulate in the unit dose includes the risk of potential side effects taking into account the route of administration (intraarticular, epidural or intraocular), the weight and age of the patient, the severity of the pain or infection, or the overall health status of the person being treated It will depend on several factors.

Advantageously, since the drug-loaded microparticles described herein are capable of near zero-order release with little initial burst, the initial loading of the drug in the unit dosage formulation can be reasonably designed according to the desired sustained release period have.

Thus, one embodiment is an injectable unit dosage form of a therapeutic for infusion into a body compartment, wherein the infusible unit dosage form comprises a plurality of microparticles, wherein the microparticles comprise (1) at least 70% A drug core, and (2) a polymeric shell encapsulating the crystalline drug core, wherein the crystalline drug core comprises at least one therapeutic agent, wherein the polymeric shell is in contact with or incompatible with the crystalline drug core, Wherein the injectable unit dosage form is capable of sustained release of the therapeutic agent for a period of 2 to 20 months while maintaining the minimum therapeutically effective concentration of the therapeutic agent in the body compartment .

In a further embodiment, the sustained release period is 2 to 9 months.

In a further embodiment, the sustained release period is 3 to 6 months.

In another embodiment, the plasma concentration of the therapeutic agent is below the quantifiable level after 7 days.

In various embodiments, the unit dosage form comprises from 0.5 to 500 mg of the therapeutic agent. In another embodiment, the unit dosage form comprises from 3 to 500 mg of the therapeutic agent.

In various embodiments, the unit dosage form further comprises a pharmaceutically acceptable vehicle. Preferably, the vehicle is combined with drug-loaded microparticles just prior to injection to avoid dissolution of the drug into the vehicle. Advantageously, due to the absence of initial rupture, any dissolution of the drug into the vehicle during normal handling times in the manufacturing process for injection is negligible. Conversely, many known drug-loaded sustained release formulations can saturate the vehicle during handling time due to initial rupture.

Usage and route of administration

The pharmaceutical compositions and dosage forms described herein are particularly adapted to be injected into the body compartment for highly localized, sustained release of the therapeutic agent. The body compartment typically contains soft tissue and / or body fluids within the enclosed or semi-enclosed. The injection is directed to the soft tissue or body fluid from which the drug-loaded microparticles are released. If desired, the implant may be guided by an imaging system, such as an ultrasound or X-ray device.

In one embodiment, the infusion is administered into the joint for sustained release of the therapeutic agent in the lubricating film or lubricant.

In another embodiment, the infusion is administered into the epidural space for sustained release of the therapeutic agent.

In a further embodiment, the infusion is administered into the eye or into the vitreous for sustained release of the therapeutic agent in the body fluids.

In a further embodiment, the infusion is performed in the natural space of the surgically created pocket or implant for sustained release of the therapeutic agent to reduce pain (e.g., anesthetic), infection (antibiotic) or solid tumor (chemotherapeutic agent) do.

In other embodiments, the pharmaceutical compositions and dosage forms may be suitable for systemic administration for sustained release of therapeutic agents, particularly chemotherapeutic agents.

As an alternative to infusion, drug-loaded microparticles may also be first attached to a pacemaker, defibrillator, orthopedic implant, artificial heart prior to implantation to reduce infection or surgical attachment.

The drug-loaded microparticles can also be combined with a mesh, film or membrane (e.g., a surgical mesh) by coating, gluing or immersion. A mesh, film or membrane introducing particulates can be placed in the body compartment or the surgical site. The route of administration is particularly adapted to antibiotic loaded microparticles.

Diseases that can be treated using the formulations of the invention

Various embodiments provide long-acting therapies or therapies for reducing pain or infection, CNS disorders, or for treating cancer / tumors.

Accordingly, one embodiment is a method of managing inflammation in a body compartment of a patient in need thereof, comprising injecting a therapeutically effective amount of a pharmaceutical composition having a plurality of microparticles into a body compartment, ) At least 70 wt% (preferably at least 90 wt%) of a crystalline drug core, wherein the crystalline drug core comprises an anesthetic agent; And (2) a polymeric shell encapsulating the crystalline drug core, wherein the polymeric shell is in contact with or incompatible with the crystalline drug core.

In various embodiments, the microparticles undergo a thermal treatment step within a temperature range of 210-230 < 0 > C.

In various embodiments, the average diameter of the microparticles is in the range of 50 占 퐉 to 800 占 퐉, or in the range of 60 占 퐉 to 250 占 퐉, or in the range of 80 占 퐉 to 150 占 퐉.

In a preferred embodiment, the diameter of the microparticles in a given pharmaceutical composition may be adjusted or selected to suit a particular route of administration. Thus, in one embodiment, at least 90% of the microparticles have a diameter in the range of 100-300 mu m, providing an injectable composition particularly suitable for epidural injection. Yet another embodiment provides an injectable composition comprising particulates wherein at least 90% of the particulates have a diameter in the range of 50 to 100 占 퐉.

In a further embodiment, the crystalline drug core constitutes at least 75%, at least 80%, at least 85%, at least 90% or at least 95% of the total weight of the particulate and the remainder of the particulate is a polymer shell.

In various embodiments, at least 90%, at least 95%, at least 98%, or 100% of the total weight of the drug core is a crystalline form of the drug.

In certain embodiments, the composition exhibits a solubility half-life of 12 to 20 hours when tested using the US Pharmacopoeia type II apparatus wherein the dissolution conditions are such that the microparticles in 200 ml of 70% methanol and 30% 3 mg.

In another embodiment, the composition exhibits a solubility half-life of 12 to 20 hours when tested using the US Pharmacopoeia type II apparatus wherein the dissolution conditions are such that fine particles in 200 ml of 70% methanol and 30% 3 mg.

Another embodiment is a method of treating a central nervous system disorder in a patient in need thereof, comprising injecting a unit dosage form having a plurality of microparticles in a patient, wherein the microparticle comprises (1) at least 70% by weight of the And (2) a polymeric shell encapsulating said crystalline drug core, wherein said crystalline drug core comprises a central nervous system (CNS) drug, said polymeric shell Wherein the polymeric shell is in contact with or incompatible with the crystalline drug core.

In a further embodiment, the injectable dosage form is capable of sustained release of the CNS drug for a period of 2 to 12 months while maintaining a minimum therapeutically effective concentration of the CNS drug in the body compartment.

A further embodiment is a method of treating an infection in a body compartment of a patient in need thereof, comprising injecting a single injection of a unit dosage formulation having a plurality of microparticles into a body compartment, wherein said particulate comprises (1) A crystalline polymeric core encapsulating the crystalline drug core, wherein the crystalline drug core comprises an antibiotic, and wherein the polymeric shell comprises at least one polymeric shell, Wherein the polymeric shell is in contact with or incompatible with the crystalline drug core.

In a further embodiment, the injectable dosage form is capable of sustained release of the antibiotic for a period of 1 to 7 days, while maintaining a minimum therapeutically effective concentration of the antibiotic in the body compartment.

A further embodiment is a method of treating cancer or solid tumors in a patient in need thereof, comprising injecting a unit dosage formulation having a plurality of microparticles (e.g., into the body compartment or systemically), wherein the microparticles are 1) a crystalline drug core of at least 70 wt% (preferably at least 90 wt%) of the microparticles, and (2) a polymeric shell encapsulating the crystalline drug core, wherein the crystalline drug core comprises a chemotherapeutic agent And wherein the polymer shell is contacted with or immiscible with the crystalline drug core.

In a further embodiment, the injectable dosage form is capable of sustained release of the chemotherapeutic agent for a period of 2 to 12 months, while maintaining the minimum therapeutically effective concentration of the chemotherapeutic agent in the body compartment or systemically.

Additional specific embodiments include the following:

The fine particles have an average diameter of 50 μm to 800 μm.

The fine particles have an average diameter of 60 mu m to 250 mu m.

The fine particles have an average diameter of 80 mu m to 150 mu m.

· Sustained release means at least 3 months.

Wherein the pharmaceutical formulation for sustained release comprises large particles of substantially pure therapeutic agent coated with at least one biocompatible or bioerodable polymer.

This reduces or eliminates the initial drug rupture.

The polymer comprises at least one of polylactic acid, polyvinyl alcohol and parylene.

Disease progression is delayed or discontinued due to the maintenance of certain low levels of drug in the body compartment.

The particles of the drug are mixed with the vehicle just prior to injection so that the particles do not have time to dissolve into the vehicle and there is no or substantially no initial rupture of the drug.

The method has fewer systemic side effects than other treatments.

Diffusion of the therapeutic agent crossing the first polymer coating exhibits pseudo-zero-order kinetics during the sustained release period.

The first polymer coating is not degraded until after the sustained release period (this is the difference compared to other sustained release formulations).

The first polymer coating maintains structural integrity during the sustained release period.

The fine particles have a maximum dimension of 50 mu m to 250 mu m.

The fine particles have a maximum dimension of 50 mu m to 150 mu m.

The therapeutic agent is hydrophobic and the first polymer coating solution is hydrophilic.

The polymeric shell comprises at least one polymer coating which is the same or different and is selected from the group consisting of sugar phosphates, alkylcelluloses, hydroxyalkylcelluloses, lactic acids, glycolic acids,? -Propiolactone,? -Butyrolactone,? -Butyrolactone, Hydroxycarboxylic acid,? -Hydroxyisobutyric acid,? -Hydroxyisobutyric acid,? -Hydroxyisobalic acid,? -Hydroxy-beta-methylvaleric acid,? -Hydroxycaproic acid, hydroxyoctanoic acid,? -hydroxystearic acid,? -hydroxystearic acid,? -hydroxyheptanoic acid,? -hydroxyoctanoic acid,? -hydroxystearic acid,? -hydroxystearic acid, Ethylene vinyl acetate, and vinyl alcohol. ≪ RTI ID = 0.0 > [0040] < / RTI >

The polymer coating is applied to the core particles by air suspension technology.

The polymer coating is applied to the core particles by a dip coating technique.

These and other modifications may be made to the system, method and article in light of the above description. In general, it should be understood that, in the following claims, the terms used should not be construed as limiting the invention to the specific embodiments disclosed in the specification and the claims, but are to be accorded the full scope of equivalents to which such claims are entitled, Should be construed as including. Accordingly, the invention is not limited by this disclosure, but instead the scope thereof is determined entirely by the following claims.

Example :

Example 1

General Procedure for Making Crystalline Drug Core

Methanol (100 mL) is added to fluticasone propionate (FP) powder (1 g) and the suspension is heated with stirring until a clear solution is obtained. The flask is left at room temperature overnight to form needle-shaped crystals. The crystals are collected using a Buchner funnel and completely oven dried at 40-50 ° C for 2 hours. Dry FP particles are added to a 80-170 탆 mesh sieve with a single layer of glass beads. A 30 to 60 탆 mesh sieve is added below the FP particle and bead containing sieve, followed by shaking for 3 to 4 minutes. The 80-170 탆 mesh body is replaced with a clean 80-170 탆 mesh body, a 2000 탆 mesh body is added to the top (optional), and the sieve stack is attached to the Buchner funnel. 2000㎛ 80 to the contents of the 170㎛ mesh sieve containing particles FP and a bead collecting gently poured into the glass bead-mesh sieve and washed with deionized water (DI-H ₂ O) in the suction. The 2000 μm mesh sieve is removed and the contents of the 80-150 μm mesh sieve are washed with DI-H ₂ O under suction. A total of 200-300 mL DI-H ₂ O is typically used. Alternatively, the contents of the sieve can be washed with Tween-80 (0.1% w / v) before washing with water, or the glass beads are replaced by grinding gently using a glass rod in a 212 mu m mesh body. The contents of 80 to 170 占 퐉 and 30 to 60 占 퐉 mesh sieve are separately dried at 40 占 폚, and the dry material is combined for polymer coating.

Example 2

Size distribution of crystalline drug core

1 g of fluticasone propionate (FP) powder (CAS 80474-14-2) was dissolved in 100 mL of ACS-grade methanol on a hot plate. The final solution was clear. The solution was cooled and left at room temperature for 24 hours. The resulting crystals were filtered, sieved, collected under a 180 μm screen (-180 μm), washed with 0.1% Tween-80 aqueous solution, washed twice with distilled water and dried at 40 ° C. for 3 hours . 940 mg of fluticasone propionate crystals (94% yield) were obtained using this procedure. Figures 4A and 4B show the average particle size and size distributions obtained.

Figure 4A is a graph showing the particle size distribution of the fluticasone propionate monodisperse distribution having an average particle size of approximately 110 mu M with a standard deviation of approximately 41 mu M. Particles of these sizes can be easily injected through a 23 g needle (inner diameter 320 μM).

As a comparison, Figure 4b is a graph showing the particle size distribution of triamcinolone acetonide (Kenalog (TM)). The average particle size is approximately 20 [mu] M. There is a relatively broad distribution with a second peak at about 1 [mu] M. The standard deviation is about 13 μM. These small particles contribute to the rupturing effect seen in this type of formulation, which is common in the prior art. Please also refer to Fig.

Example 3

General Procedure for Coating Crystalline Drug Cores

The dried FP crystals prepared according to Example 1 were dispersed in polyvinyl alcohol (PVA, 25% v of DI-H ₂ O, v) in a model VFC-LAB microbench top fluidized bed coater system / v 2% w / v in isopropyl alcohol)

Air flow, 50 to 60 L min ^-1 ;

Nozzle air, 5.0 to 25 psi;

Pump speed, 10 to 35 rpm;

Inlet temperature, 99 캜;

Exhaust temperature, 35 to 40 占 폚;

Spray on / off cycle: 0.1 / 0.3 min.

The PVA content is measured periodically by quantitative ¹ H nuclear magnetic resonance (NMR) spectroscopy by comparing the relative signal intensity of FP and PVA resonance in the drug product with the corresponding signal from the calibration standard (see Example 3). The final target PVA concentration in the drug product is in the range of 0.1 to 20% w / w, preferably 2 to 10% w / w. The coating of the particles continues until the desired amount of PVA is achieved. The coated particles are then dried in an oven at 40 占 폚 for 1 hour. The dried coated particles are sieved in a sieve stack defined by a 150 mu m mesh and a 53 mu m mesh sieve.

Example 4

NMR analysis to determine the drug content in the microparticles

NMR analysis is used to determine the amount of drug core and polymer shell in the particulate by correcting it with a known amount of sample of the pure drug.

The NMR system includes a Bruker BBO 300 MHz Sl 5 mm with a Bruker Spectrospin 300 MHz magnet, a Bruker B-ACS 120 autosampler, a Bruker Avance II 300 console, and a Z gradient probe. The calibration curves were prepared using five samples of known genpluticasone propionate and the PVA concentrations were prepared in NMR grade d6-DMSO. Proton (1H) NMR was performed on the following two samples: a second containing only the pure fluticasone propionate and a second containing the PVA-coated fluticasone. Each sample was manually loaded and rotated at 20 Hz inside the magnet. The probes were adjusted and matched for proton (1H) NMR. The magnet manually deepens the first sample in the magnet. Each sample was integrated into 1024 scans for 1.5 hours. The fluticasone peak was incorporated from 5.5 ppm to 6.35 ppm and the PVA peak was integrated from 4.15 ppm to 4.7 ppm (see Figure 5). Using this method, it was determined that the finished coated fluticasone particles contained 2.1% PVA of the total weight of the coated particles. Assuming a spherical particle shape and an average particle diameter of 100 mu m, this represents a coating thickness of approximately 7 mu m.

Example 5

In vitro dissolution analysis

Add the dissolution medium and 3 mg of PVA-coated FP particles to each vessel (1000 mL volume) of the USP Type II dissolution system. The dissolution medium typically consists of an alcohol-water mixture of 5 to 90% v / v, wherein the alcohol may be methanol, ethanol and isopropanol. The volume of dissolution medium used is in the range of 50 to 750 mL. The temperature of the dissolution medium is maintained at room temperature or at a temperature within the range of 5 to 45 占 폚. An aliquot is removed from the dissolution medium at a predetermined point in time and the sample is stored for subsequent analysis by, for example, UV-visible light absorption spectroscopy or high performance liquid chromatography.

A specific set of dissolution conditions is as follows:

Drug for dissolution: 3 mg PVA-coated FP particles;

Dissolution medium: 200 ml of 70% v / v ethanol and 30% v / v water;

Melting temperature: 25 ℃

Example 6

Influence on heat treatment and dissolution

The coated microparticles prepared according to Example 2 were thermally processed, i.e., heat treated, for a specified period of time. Specifically, the interior of the borosilicate Petri dish was lined with aluminum foil and a single layer of PVA-coated FP particles was spread. The dish was wrapped with perforated aluminum foil. The oven was preheated to the desired set point and the sample was heat treated for a predetermined amount of time. The temperature set points were 160 캜, 190 캜, 220 캜 and 250 캜.

FIG. 3A shows the dissolution profile of the fine particles subjected to the heat treatment at the temperature. The dissolution conditions were as follows: 3 mg of PVA-coated FP microparticles were dissolved in 200 ml of dissolution medium at 70 ° C v / v ethanol and 30% v / v water at 25 ° C. The resulting concentration-time data is analyzed (e. G., One phase decay model) to obtain the dissolution half-life t (shown in FIG. 3B).

As shown in Figure 3A, the microparticles heat-treated at 220 占 폚 have the slowest and the slowest initial emis- sions as compared to the microparticles treated at temperatures of 220 ° C or less.

Figure 3b shows the dissolution half-life of the microparticles of Figure 3a. As shown, the microparticles heat-treated at 220 占 폚 have a significantly longer dissolution half-life (12 to 20 hours) than the other microparticles (all less than 8 hours).

Example  7

Sustained Release (SR) Formulation for Animal Studies (Volume)

Dry FP crystals were prepared according to Example 1 and were dispersed in polyvinyl alcohol (PVA, 25% in DI-H ₂ O) in a Model VFC-LAB microbench top fluid bed coater system (Vector Corporation) 2% w / v in v / v isopropyl alcohol): air flow, 50 to 60 L / min; Nozzle air, 23 psi; Pump speed, 15 rpm; Inlet temperature, 99 캜; Exhaust temperature, 35 to 40 占 폚; Spray on / off cycle: 0.1 / 0.3 min.

Subsequently, the resulting fine particles were heat-treated at 130 캜 for 3 hours.

The fine particles have an average diameter in the range of 60 to 150 mu m. The PVA content of the resulting microparticles was 2.4% when analyzed by NMR analysis according to the method described in Example 4. [

Example  8

Sustained release (SR) formulation for animal studies (dogs)

Dried FP crystals were prepared according to the above procedure and analyzed using polyvinylalcohol (PVA, 25% v of DI-H ₂ O v (v) in a model VFC-LAB microbench top fluidized bed coater system 2% w / v in isopropyl alcohol / v): air flow, 50 to 60 L / min; Nozzle air, 8.0 psi; Pump speed, 25 rpm; Inlet temperature, 99 캜; Exhaust temperature, 35 to 40 占 폚; Spray on / off cycle: 0.1 / 0.3 min.

Subsequently, the produced fine particles were heat-treated at 220 ° C for 1.5 hours.

The fine particles have an average diameter in the range of 60 to 150 mu m. The PVA content of the resulting microparticles was 4.6% when analyzed by NMR analysis according to the method described in Example 4.

Fig. 6 shows the dissolution profile of the fine particles prepared by Example 8 compared to the fine particles prepared by Example 7. Fig. In addition, Figure 6 further shows the dissolution profile of another corticosteroid (triamcinolone acetonide) and fluticasone propionate powder (uncoated, amorphous or very small crystals of less than 10 mu m). The coated FP microparticles (Examples 7 and 8) all exhibited a much longer dissolution half-life and smaller initial burst than FP powder and triamcinolone acetonide. In addition, the fine particles heat-treated at 220 deg. C were produced similarly, but appeared to have a much longer dissolution half-life than the fine particles heat-treated at 130 deg. C (Example 7).

The dissolution conditions were as follows:

Drug for dissolution: 3 mg PVA-coated FP particles

Dissolution medium: 200 ml of 70% v / v ethanol and 30% v / v water;

Melting temperature: 25 ℃.

Example 9

Suspension formulation / infusion potential.

Optimized suspension formulations of coated particles were obtained using an iterative process whereby different suspension solutions at various concentrations were evaluated for their ability to retain coated particles in suspension. The most uniformly dispersed formulations were then injected through needle sizes ranging from 18 to 25 gauge. The particle transfer efficiency was measured by HPLC. A 1% CMC solution provided the maximum suspension, and a 23 gauge needle provided adequate injection efficiency.

Aseptic . The polymer-coated fluticasone particles were steam sterilized in an amber vial (122 캜, 16 psi, 30 min). The sterilization process did not affect the chemical composition of the formulations according to < 1 > H NMR spectroscopy and HPLC analysis. Please refer to Fig. In vitro studies in a 500 mL USP Type II system confirmed that the sterile material had the same fluticasone release profile as the same material prior to autoclaving.

Example 10

In vivo pharmacokinetics (PK) analysis (volume)

In the non-GLP search study, local toxicity and drug concentration levels were assessed for 3 months (n = 4) after single intra-articular injection into the left quadruple knee joint using a 23 G needle of a tuberculin syringe. The injectable dosage form was 0.5 mL of 20 mg extended release fluticasone propionate (EP-104) prepared according to Example 7. [

Clinical observations were performed throughout the study and histopathology was performed at the end of the study to assess local toxicity. To assess the level of treated knee fluticasone propionate concentration, lubricant samples were collected at designated time points. Plasma concentrations were measured by collecting blood throughout the study. Plasma fluticasone levels were measured by HPLC-MS (see Mistry N, et al., Journal of Pharmaceutical and Biomedical Analysis 16 (4): 697-705,1997). Mortality, morbidity, and body weight were also assessed.

There were no changes during the clinical observation and no histopathologic changes occurred anywhere in the knee after 3 months. There was no mortality or morbidity, and the amount was increased throughout the study.

Fluticasone propionate concentrations were detected in the lubricant at 3 months (n = 4; 11.51, 9.39, 13.22, and 18.89 ng / mL). Plasma concentration levels were lower than lube fluids and decreased at a greater rate. Plasma fluticasone propionate concentrations were less than or equal to 0.3 ng / mL beginning at day 0 at the limit of quantitation (BQL) or at day 70. Plasma and lubricant concentrations throughout the study are provided in FIG.

Notable is the absence and sustained local concentration of rupture achieved during the duration of the experiment. The reported EC50 of fluticasone propionate is 7 to 30 pg / ml (see Mollmann H, et al., Pharmacokinetic and pharmacodynamic evaluation of fluticasone propionate after inhaled administration, European Journal of Clinical Pharmacology Feb; 53 (6): 459 -67, 1998). Significantly, after 90 days, the local concentrations of FP in the lubricant remained significant (n = 4; 11.51, 9.39, 13.22, and 18.89 ng / mL) and above the EC50 level, while plasma concentrations were no longer detectable (Plasma concentration was BQL at 70 days).

As a comparison, the release of triamcinolone hexasatonide (40 mg) from a human subject is also plotted in Figure 7 (Derendorf H, et al., Pharmacokinetics and pharmacodynamics of glucocorticoid suspensions after intra-articular administration, Clinical Pharmacology and Therapeutics Mar ; 39 (3): 313-7 (1986)). As shown, triamcinolone hexasatonide release shows a rapid decrease after significant initial rupture. The emission duration is significantly shorter than the coated FP microparticles described herein despite having a much higher initial capacity.

The form of the PK curve of the corticosteroid microparticles is substantially different from that of triamcinolone hexasatonide. A slow rise over a period of 60 days and a nearly constant release confirm a pseudo-zero order release mechanism whereby the corticosteroid drug is able to maintain a saturated solution in the polymer shell, regardless of the original drug loading It is released at an almost constant rate (eg, for 60 days).

Animals were euthanized at 90 days, incised joints and sent for histology. There were no noted safety or toxicity issues in the clinical investigation. Histological examination of the implanted joints showed no abnormality (Figures 8a, 8b, and 8c).

Example 11

In vivo pharmacokinetic (PK) studies ()

An extended release fluticasone propionate formulation (EP 104IAR) was prepared according to Example 8. The in vivo release properties were evaluated within the knee of a beagle dog (n = 32) during a 60 day study. Two groups of 16 male and female dogs were evaluated. Groups 1 (n = 8 males and 8 females) were administered a target dose of 0.6 mg EP-104 IAR by intra-articular injection (low dose group). Group 2 was administered a target dose of 12 mg EP-104 IAR (high dose group) by intra-articular injection.

Lubricants and plasma were collected at 7, 29, 46, and 60 days after injection, and cartilage tissue drug concentrations and microscopic changes were also evaluated at these times. Mortality check, clinical observation, and weight measurement were performed. Pre-dose, and 3, 5, and 7 days; Blood was collected for analysis of plasma from all live animals twice weekly (including the autopsy day) until the autopsy. Two animals / sex from each group were euthanized at 7, 29, 46 or 60 days. Prior to autopsy, the lubrication fluid was collected for biological analysis.

result:

In the low dose group, there was no measurable concentration of free fluticasone propionate in plasma at any sampling time, indicating that the drug remained in the joint. See FIG.

In the high dose group, measurable at 3 days after injection but low plasma concentrations occurred and ranged from 0.2 to 0.5 ng / mL. On the other hand, the local concentrations of lubricant and drug in the tissues were significantly higher over the entire study period. See FIG.

The highest concentrations of fluticasone propionate in the lubricant generally occurred on day 7 in both dose groups, ranging from 3 to 25 ng / mL in the low dose group (Figure 9) and 179 to 855 ng / mL in the high dose group (Fig. 10). In the low dose group, measurable fluticasone propionate concentration in the lubricant was detected at 60 days, but the concentration was below the limit of quantification (1.0 ng / mL) at this time of collection. At 60 days, the concentration of fluticasone propionate in the lubricant of the high capacity animal was 97 to 209 ng / mL.

Example 12

Comparison results -

Figure 6 shows the influence on the dissolution characteristics by the heat treatment step during the formation of fine particles. Particularly, the fine particles subjected to a precise heat treatment step (220 ° C for 1.5 hours) exhibited a significantly longer dissolution half-life than the fine particles subjected to the heat treatment step at much lower temperatures (130 ° C for 3 hours). The results show that the precise heat treatment step at 220 占 폚 eventually resulted in certain structural changes in the polymer shell that altered its permeability characteristics.

Fine particles subjected to different heat treatment steps were used in both studies (heat treated at 130 캜) and open studies (heat treated at 220 캜), and their sustained release behavior in vivo was discussed in Examples 9 and 10, respectively have.

Figure 11 shows plasma concentrations measured in both studies compared to open studies. As shown, the plasma concentrations in both studies were significantly lower (0.25 mg / kg) than in the open study, despite the fact that the doses were substantially lower (0.25 mg / kg) And then showed a much higher concentration. Moreover, plasma concentrations in dogs were mostly constant before they became undetectable. Conversely, the plasma concentration in the amount showed a further variation over the period of release. The results show that the heat treatment step during particulate formation significantly affected the in vivo release behavior as much as it was done for in vitro dissolution behavior (see Example 8).

Example 13

Absence of initial burst

Fluticasone propionate fine particles were prepared according to Example 8. Microparticles with an average diameter in the range of 50-100 mu m were used to study plasma pharmacokinetics (PK) in the first two days after injection. Two groups (n = 3 per group) were injected with 2 mg dose (low dose) and 60 mg dose (high dose), respectively.

Most sustained release formulations are expected to exhibit an initial burst or peak within the plasma within the first 48 hours after administration. However, unexpectedly, the FP sustained release formation according to embodiments of the present invention does not exhibit an initial burst. Figure 12 shows the complete absence of initial tear or peak within the first two days in the high dose group, and all samples were below the quantitation limit (although measurable). In the low dose group, only a single sample was detectable, but less than quantification. Thus, the sustained release formulations described herein are capable of delivering highly localized delivery of a corticosteroid (e. G., Fluticasone propionate) to a less than potentially clinically significant HPA axis inhibition, Steroids can be maintained. Importantly, the complete absence of initial burst even in high dose groups indicates that in vivo release follows a zero-order or quasi-zero order pattern.

All of the foregoing US patents, US patent application publications, US patent applications, foreign patents, foreign patent applications, and non-patent publications mentioned in and / or listed in all of the abovementioned references herein are incorporated herein by reference in their entirety.

Claims (19)

A pharmaceutical composition comprising a plurality of microparticles,
When the fine particles
(1) A drug core comprising at least 90 wt% of a particulate, wherein the drug core comprises at least one therapeutic agent selected from an anesthetic, an antibiotic, a central nervous system (CNS) agent, or a chemotherapeutic agent; And
(2) a polymer shell encapsulating the drug core, wherein the polymer shell is in contact with or immiscible with the drug core,
Wherein the plurality of microparticles have an average diameter in the range of 80 占 퐉 to 150 占 퐉 and a standard deviation of less than 50% of the average diameter. The pharmaceutical composition of claim 1, wherein the plurality of microparticles have an average diameter of 75 占 퐉 and a standard deviation of less than 50% of the average diameter. 3. The pharmaceutical composition according to claim 2, wherein the plurality of microparticles have an average diameter of 150 mu m and a standard deviation of less than 50% of the average diameter. The pharmaceutical composition according to any one of claims 1 to 3, wherein 90% or more of the fine particles have a diameter in the range of 100 to 300 mu m. 4. The pharmaceutical composition according to any one of claims 1 to 3, wherein at least 90% of the microparticles have a diameter in the range of 50 to 100 mu m. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the therapeutic agent is an anesthetic agent. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the therapeutic agent is a central nervous system agent. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the therapeutic agent is an antibiotic. 6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the therapeutic agent is a chemotherapeutic agent. A method for managing pain in a body compartment of a patient, comprising injecting a therapeutically effective amount of the pharmaceutical composition of claim 6 into a body compartment of a patient in need thereof. 8. A method of treating a central nervous system disorder in a patient in need thereof comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 7 to a patient in need thereof. 12. The method of claim 11, wherein the pharmaceutical composition is capable of sustained release of the CNS drug for 2 to 12 months while maintaining a minimum therapeutically effective concentration of the CNS drug in the patient. 9. A method of treating an infection in a body compartment of a patient, comprising administering the pharmaceutical composition of claim 8 to a body compartment of the patient in need thereof. 14. The method of claim 13, wherein said pharmaceutical composition is administered by injection. 14. The method of claim 13, wherein the pharmaceutical composition is formulated with an implant, a surgical mesh, a surgical film, or a surgical membrane. 16. A method according to any one of claims 13 to 15, wherein the administered pharmaceutical composition is capable of sustained release of the antibiotic for a period of from 1 to 7 days while maintaining a minimum therapeutically effective concentration of the antibiotic in the body compartment. , Way. 11. A method of treating cancer or a tumor in a patient in need thereof, comprising administering the pharmaceutical composition of claim 9 to a patient in need thereof. 18. The method of claim 17, wherein said pharmaceutical composition is administered by injection into a body compartment that is systemically or adjacent to a solid tumor. 19. The method of claim 17 or 18, wherein said pharmaceutical composition is capable of sustained release of said combination therapy agent for a period of 2 to 12 months while maintaining a minimum therapeutically effective concentration of the chemotherapeutic agent in said body compartment .

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